Clefts of the lip and palate are developmental craniofacial abnormalities that result from a failure of neural crest cells to migrate properly. As a group, clefting disorders are comprised of those that are isolated to facial clefts only (non-syndromic) and those in which the facial cleft is part of a well-defined syndrome of additional anomalies. Non-syndromic clefting has been shown to be associated with cognitive dysfunction. In syndromic clefting disorders, cognitive dysfunction is ubiquitous and often severe. The fact that clefts of the lip and/or palate are associated with brain abnormalities is intuitive as the development of the brain and face are intimately related. However, the systematic study of the types of brain anomalies present in patients with clefts of the lip and/or palate (and the functional consequences thereof) has been almost completely overlooked. This is an application for a Mentored Patient Oriented Research Career Development Award. During the award period, the candidate proposes an organized program of training and supervised research. While the candidate has training in structural imaging of the brain, she requires additional training in developmental biology, cognitive assessment, clinical assessment of genetic syndromes, and molecular and quantitative genetics. This training will be integrated with a research project in which the candidate proposes to phenotype Van der Woude Syndrome (VDWS), an autosomal dominant disorder manifesting as isolated clefts of the lip and/or palate and lip pits, by: 1) evaluating brain structure of patients using Magnetic Resonance Imaging, and 2) evaluating brain function in these patients using neuropsychological tests. In addition, these patients with VDWS will be screened for microdeletions using an allele loss assay. This will allow direct phenotype/genotype correlations to explore the relationship between the genetic determinants of facial clefting and brain structure/function. These findings will lead to a better understanding of the neurobiology underlying the cognitive dysfunction that significantly impairs the life of many patients with facial clefts. In turn, these findings may lead to early intervention with detection and treatment of cognitive deficits. This award would provide the candidate with the necessary background for further studies into brain structure and function in other craniofacial syndromes as well as into the genetic determinants of brain development. This award will also provide the candidate with the background necessary for ongoing research and funding leading to an independent research career.